Project Summary Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in the United States, affecting approximately 80 million adults. The leading cause of death in NAFLD is coronary artery disease (CAD) and accounts for >25% of deaths. Despite the high incidence of CAD-related mortality, little is known about NAFLD specific CAD pathogenesis. Thus, there is a pressing need to elucidate the pathophysiology linking NAFLD and CAD. The aim of this proposal is to evaluate a specific metabolite, anandamide (AEA) in NAFLD and CAD and to begin to define the metabolomic signatures of CAD in NAFLD. We have previously shown that NAFLD is associated with several important CAD risk factors including a high frequency of atherogenic dyslipidemia, characterized by high levels of small dense LDL. We have also shown that dyslipidemia improves with NASH resolution but does not resolve entirely. Further, we have identified several novel factors associated with CAD in NASH including serum sodium, serum albumin and model for end-stage liver disease (MELD) score. However, these identified factors do not fully account for the increased risk of CAD in NAFLD. Thus, we have undertaken a metabolomic screen in our patients and found that the endocannabinoid AEA is associated with radiographic NAFLD, histologic NASH and cardiometabolic risk factors including weight circumference, insulin resistance and body mass index. Thus, AEA may serve as a link between NAFLD and CAD development and warrants further evaluation. We also seek to more comprehensively evaluate the complex relationship between CAD and NAFLD by evaluating full metabolomic profiles in those with CAD and NAFLD and those with NAFLD alone. The larger goal of this proposal is to build further preliminary data in preparation for an R01 application over the next 12-24 months. The planned R01 will focus on the metabolomic profiles in individuals with NAFLD that predict the development of incident coronary artery disease (CAD) and CAD-related death as well as to assess differences between metabolomic profiles before and after the development of CAD. Elucidation of these profiles will allow for the development of a CAD risk profile in NAFLD and provide understanding into the pathogenesis of CAD in NAFLD. Ultimately, we hope to improve our understanding of CAD in NAFLD to improve CAD prevention and decrease CAD-related mortality in NAFLD.